Dual-Targeting Liposomes Based on Ginsenoside Rg3 for Intercepting the Metastatic Cascade in Breast Cancer

Abstract Metastatic progression remains the primary cause of mortality in triple-negative breast cancer. However, unmodified cholesterol-based liposomes displayed inherent limitations, such as pharmacological inertness and sole reliance on passive targeting, that preclude the selective elimination of residual tumor lesions or circulating tumor cells after surgery, thereby failing to interrupt the multi-step metastatic cascade. Herein, we present a dual-targeting cRGD-Rg3@DOX liposomal designed to overcome these limitations for post-TNBC surgical therapy. This smart liposome was fabricated via a single-step microfluidic synthesis, wherein ginsenoside Rg3 strategically replaces cholesterol as both a structural stabilizer and a bioactive therapeutic targeting component. This novel design achieves dual active targeting via Rg3-mediated GLUT1 recognition and cRGD binding to ανβ3 integrin, resulting in superior cellular specificity and uptake. A fourfold increase in targeting efficiency to lung metastatic sites in vivo is critical for eradicating both postoperative residual tumor cells and circulating tumor cells. In a murine 4T1 metastasis model, the cRGD-Rg3@DOX liposome exerts a multi-stage intervention on the metastatic cascade, significantly inhibiting epithelial−mesenchymal transition and concurrently downregulating key prometastatic factors to eliminate postoperative residual lesions. This synergistic multi-targeted action suppresses the formation of pulmonary metastatic colonies, reduces colony numbers from 139 to 31, extends median survival time from 22 to 43 days, and markedly reduces doxorubicin-induced cardiotoxicity. This cRGD-Rg3@DOX liposome presents a robust, dual-targeted nanotherapeutic strategy that effectively suppresses lung metastases and mitigates pro-metastatic factors, offering a promising paradigm for intercepting metastatic progression in the preclinical TNBC mice model.